Arthritis Care & Research
Vol. 65, No. 6, June 2013, pp 1005–1013
DOI 10.1002/acr.21988
© 2013, American College of Rheumatology
CLINICOPATHOLOGIC CONFERENCE
Two Systemic Lupus Erythematosus Patients With
Severe Pleurisy: Similar Presentations, Different
Causes
CAROLINE M. GULATI,1 MICHAEL J. SATLIN,1 CYNTHIA M. MAGRO,1
CASE PRESENTATIONS
Case 1
History of the present illness. A 25-year-old woman
was diagnosed with systemic lupus erythematosus (SLE) 2
years prior to admission, after she presented with fever,
malaise, lymphadenopathy, arthritis, myalgias, malar rash,
and positive serologies for antinuclear antibody (ANA)
and anti– double-stranded DNA (anti-dsDNA). Additional
serology tests were negative for anti-Ro/SSA, anti-La/SSB,
RNP, and Sm antibodies, as well as antiphospholipid an-
tibodies (aPL). She was treated with intermittent courses
of glucocorticoids (GC) for disease flares. Eight months
before admission, she had a severe flare that manifested
with high fevers, weight loss, delirium, spastic bladder,
and non-nephrotic proteinuria. She was ultimately diag-
nosed with gray matter transverse myelitis of the conus
medullaris and lupus nephritis. She was treated aggres-
sively with pulse GC and intravenous (IV) cyclophos-
phamide (CYC), which led to resolution of all symptoms.
After completion of a 6-month course of IV CYC, she was
maintained on 20 mg of prednisone. One month prior to
admission, she was admitted to another hospital with left-
sided pleurisy, dyspnea, and high fever. A chest computed
tomography (CT) scan excluded pulmonary embolism, but
showed bilateral lung lower lobe consolidations with
pleural effusions (left larger than right) and a small fluid
collection adjacent to her spleen. Her blood cultures grew
Salmonella. Her symptoms improved with cefepime and
Supported by the Mary Kirkland Center for Lupus Re-
search.
1
Caroline M. Gulati, MD, Michael J. Satlin, MD, Cynthia
M. Magro, MD: New York Presbyterian Hospital and Weill
Cornell Medical College, New York; 2Kyriakos A. Kirou,
MD: Hospital for Special Surgery, New York, New York.
Dr. Kirou has received consultant fees (less than $10,000)
from Exagen Diagnostics.
Address correspondence to Kyriakos A. Kirou, MD, Mary
Kirkland Center for Lupus Research, Hospital for Special
Surgery, 535 East 70th Street, New York, NY 10021. E-mail:
kirouk@hss.edu.
Submitted for publication November 28, 2012; accepted in
revised form February 12, 2013.
AND KYRIAKOS A. KIROU2
high-dose GC, and she was discharged home 2 weeks later
on 60 mg of daily prednisone and oral levofloxacin for a
total of 3 weeks of antibiotics. In addition, she was dis-
charged on trimethoprim/sulfamethoxazole (TMP/SMX)
160/800 mg 3 times weekly for Pneumocystis jiroveci
pneumonia (PCP) prophylaxis. One week before her cur-
rent admission, she was started on 1,000 mg of mycophe-
nolate mofetil (MMF) daily. She then presented to our
hospital with acute left-sided pleuritic chest pain, dys-
pnea, and arthralgias. She did not have fever or cough.
Medical history. She had a history of mild asthma and
hypothyroidism.
Family and social history. Her family history was un-
remarkable except for a maternal aunt who also had SLE.
There was no history of smoking, alcohol, or illicit drug
use.
Medications. Her home medications included predni-
sone 40 mg daily, MMF 500 mg twice daily, hydroxychlo-
roquine (HCQ) 200 mg daily, TMP/SMX 160/800 mg 3
times weekly, esomeprazole 40 mg, and levothyroxine 50
␮g daily. She was not taking any supplements.
Review of systems. She denied fevers, chills, cough,
dyspnea, leg swelling, joint pain, skin rash, or oral ulcers.
Physical examination. She appeared to have Cushin-
goid features, but was afebrile and not hypoxic. Her blood
pressure was 140/90 mm Hg and her heart rate was 90
beats per minute. She had decreased breath sounds over
her left lower lung field. She had a normal cardiac exam-
ination and no hepatosplenomegaly, lymphadenopathy,
rashes, or ulcers. She had a normal neurologic examina-
tion and no joint swelling or tenderness.
Laboratory and radiologic evaluation with hospital
course. Her initial blood tests are shown in Table 1. She
had non-nephrotic proteinuria and microscopic hematuria
without a rise in her baseline creatinine level. A kidney
biopsy was not performed because her nephritis appeared
1005
1006 Gulati et al

Table 1. Laboratory values at initial presentation*

Normal
Case 1 Case 2 values

WBC count, ⫻ 103/␮l 11.5 9.8 3.5–10.7

Absolute lymphocyte count, ⫻ 103/␮l 0.3 0.2 0.9–5.2
Hemoglobin, gm/dl 9.7 11.3 11.5–16
Platelet count, ⫻ 103/␮l 275 160 160–400
Creatinine, mg/dl 1.3 1.62 0.44–1.03
Albumin, mg/dl 2.7 3.3 3.5–4.8
Globulin, mg/dl 2.9 1.8 1.8–3.3
LDH, IU/liter 264 209 105–333
ESR, mm/hour 86 46 4–20
Complement C3, mg/dl 71 109 79–152
Complement C4, mg/dl 30 29 16–38
Anti-dsDNA Positive Negative Negative
Urine protein:creatinine ratio, gm 1.78 0.76 ⬍0.2
Urine RBC count, per hpf 17 22 0–4
Urine WBC count, per hpf 8 5 0–5
Pleural fluid
LDH, IU/liter 274 280
Total protein, mg/dl 3.2 2.9
Glucose, mg/dl 107 120
pH 7.5 7.5
RBC count, per ␮l 30,000 1,530
WBC count, per ␮l 21,000 2,850
Neutrophils, % 81 81
Cytology Reactive mesothelial cells

* WBC ⫽ white blood cell; LDH ⫽ lactate dehydrogenase; ESR ⫽ erythrocyte sedimentation rate;
anti-dsDNA ⫽ anti– double-stranded DNA; RBC ⫽ red blood cell; hpf ⫽ high-power field.

mild and the results were unlikely to change her manage-
ment. CT imaging of the chest, abdomen, and pelvis again
excluded pulmonary embolism, but showed a left-sided
pleural effusion with adjacent lung consolidation and a
parasplenic fluid collection. Her pleural fluid was sampled
and showed an exudative process with a neutrophilic in-
flammatory response (Table 1) without organisms on Gram
stain or culture. A transthoracic echocardiogram was nor-
mal. Her GC dose was increased to 16 mg of IV methyl-
prednisolone (IVMP) every 8 hours and she received an
additional 500 mg dose of IVMP. MMF was continued at
the same dose. IV oxacillin was initiated after 1 of 2 sets of
blood cultures grew Staphylococcus warneri. Despite
these interventions, her symptoms did not improve. Bron-
choscopy was performed 9 days after admission and bron-
choalveolar lavage (BAL) yielded nonbloody, cellular,
frothy fluid. The fluid was negative for bacterial, fungal,
and mycobacterial pathogens, but was positive for influ-
enza A by polymerase chain reaction (PCR). Oseltamivir
was prescribed for a 5-day course. Transbronchial biopsies
(TBBX) were unable to be performed because of hypoxia
during the procedure. Her abdominal fluid was sampled
on day 14 by CT guidance to exclude an abscess and
showed serosanguinous fluid, consistent with serositis.
She had a repeat chest CT scan 16 days after admission
that showed loculations within a moderate left pleural
effusion and an unchanged left lower lobe consolidation
despite high-dose GC, IV oxacillin, and oseltamivir (Figure
1A). The patient underwent video-assisted thoracoscopic
surgery (VATS) 21 days after admission for a more defin-
itive diagnosis.
Case 2
History of the present illness. A 23-year-old woman
was diagnosed with SLE 10 months before admission, after
she presented with high fever, malaise, and alopecia. She
was found to have pancytopenia, a pericardial effusion,
and International Society of Nephrology/Renal Pathology
Society class IV-G (A) lupus nephritis based on renal bi-
opsy. Her serologic tests showed low complement levels,
as well as antibodies to dsDNA, SSA, SSB, RNP, and Sm.
aPL tests were negative. She improved after treatment with
high-dose GC and one dose of IV CYC, and was started on
MMF maintenance therapy. Four months before admis-
sion, while receiving prednisone 15 mg daily, she devel-
oped autoimmune hemolytic anemia. Her prednisone dos-
age was increased to 50 mg/day and HCQ was added to her
regimen. Eight weeks before admission, she developed a
new severe left-sided pleuritic chest pain that prompted
admission at another hospital. She was noted to have a
peripheral mass-like left lower lobe pulmonary infiltrate
on a chest CT scan. She underwent a CT-guided needle
biopsy that revealed “organizing pneumonia with diffuse
alveolar damage.” She was treated with a short course of
IV antibiotics, her prednisone dosage was increased from
35 mg to 50 mg/day, and MMF was continued. One week
after discharge, her chest pain worsened and she was
readmitted and treated with IV vancomycin and piperacil-
lin tazobactam, followed by oral levofloxacin, for a total of
10 days of antibiotics. After initial improvement, her pleu-
ritic chest pain returned and she developed a new dry
cough, prompting her first admission to our hospital. Her
Clinicopathologic Conference
Figure 1. A, Consolidation with loculated effusion in case 1. B,
Dense nodular consolidations within larger consolidation of the
left lower lobe in case 2. Smaller nodules were seen near the
hilum and subpleurally. Associated pleural and pericardial effu-
sions are shown.
chest CT scan showed a left lower lobe and inferior lingu-
lar lung consolidation with additional foci of more nodu-
lar consolidations (increased since 5 weeks earlier). In
addition, there were right upper lobe scattered ground-
glass densities and a small loculated left-sided pleural
effusion that was not large enough to be sampled (Figure
1B). She was started empirically on IV vancomycin and
piperacillin tazobactam, TMP/SMX was initiated for PCP
prophylaxis, and her prednisone (50 mg/day), MMF, and
HCQ doses were unchanged. Bronchoscopy with BAL was
performed and yielded nonbloody, frothy fluid. Lavage
studies revealed rhinovirus by PCR and 16,000 copies/ml
of cytomegalovirus (CMV) DNA. Pathology from a fluoro-
scopically guided TBBX showed lymphocytic infiltration
of the interstitium. There was also focal fibrin deposition
within septal and alveolar spaces. On direct immunofluo-
rescence (DIF), there was IgG, IgA, IgM, C3, C1q, fibrino-
gen, and C5b–9 granular staining within the septa and
septal capillaries. There were no intracellular inclusions
to suggest CMV infection. The pathology findings were
interpreted as interstitial pneumonitis with significant
septal capillary injury due to SLE. Blood and sputum
cultures, as well as bacterial, fungal, Pneumocystis, and
mycobacterial stains and cultures of the BAL fluid and
biopsy material, were negative. In addition, Histoplasma
1007
and Legionella urinary antigens, galactomannan and cryp-
tococcal serum antigens, and QuantiFeron-TB Gold testing
were negative. Because of persistent pleurisy, she was
treated with 1,000 mg of IVMP daily for 3 days, 750 mg of
IV CYC for 1 day, and 1,000 mg of IV rituximab for 1 day,
and was discharged the next day. She was also placed on
valganciclovir for the CMV detected on BAL fluid. The day
after discharge, she developed rapid deterioration of her
left chest pain and dyspnea and was readmitted to our
hospital.
Medical history. She had no significant medical history
except for her SLE and complications of the disease, in-
cluding chronic kidney disease with a baseline creatinine
level of 1.6 mg/dl, autoimmune hemolytic anemia, lym-
phopenia, and arthralgias.
Family and social history. There was no family history
of SLE or other autoimmune diseases. She had no history
of smoking, alcohol, or illicit drug use.
Medications. Her home medications included predni-
sone 40 mg daily, HCQ 200 mg daily, TMP/SMX 80/400
mg daily, as well as carvedilol 12.5 mg twice daily, sim-
vastatin 20 mg once daily, darbepoetin alfa, omeprazole 40
mg once daily, risedronate, calcium, and vitamin D.
Review of systems. She denied fevers, chills, or night
sweats. Her weight was stable. She experienced throat
pain and was found to have thrush. She had no rash,
arthritis, or lymphadenopathy.
Physical examination. She appeared to have Cushin-
goid features and seemed acutely ill. Her blood pressure
was 110/60 mm Hg and her heart rate was 115 beats per
minute and regular. She was afebrile, but hypoxic to 85%
on room air. She had decreased breath sounds and a rub at
the left lung base. She had a normal cardiac and abdominal
examination. She had no rashes except for some acne due
to GC. She was neurologically intact and had no signs of
synovitis on joint examination.
Laboratory and radiographic evaluation with hospital
course. Laboratory tests upon her initial admission are
shown in Table 1. She had anemia with mild renal insuf-
ficiency (at her baseline). She had mild proteinuria and
microscopic hematuria. Her blood cultures were negative.
A chest radiograph showed near complete opacification of
the left hemithorax with a rightward mediastinal shift
(Figure 2). A chest CT scan showed a large partially locu-
lated left pleural effusion with near complete collapse of
her left lung, a small right pleural effusion, and small to
moderate pericardial effusion. She was started empirically
on IV piperacillin tazobactam, her prednisone dosage was
decreased to 20 mg/day, and TMP/SMX prophylaxis and
HCQ were continued. A chest tube was placed to drain her
enlarging pleural effusion. Fluid analysis showed an exu-
dative process, normal complement levels, and a negative
ANA. No lupus erythematosus cells were found. Pleural
fluid Gram, potassium hydroxide, and acid-fast stains
1008
Figure 2. Two days before (A) and 3 days after (B) pulse glucocorticoid therapy in
case 2.
were negative and blood and urine cultures were negative.
CMV from plasma showed 201 copies of DNA per ml.
Given the size of the effusion, progressive hypoxia, and
lack of a diagnosis, VATS was performed 6 days after
admission for decortication and biopsies of the lung and
pleura.
Case summaries
Both cases describe patients with severe SLE requiring
heavy immunosuppression who developed severe pleu-
risy while receiving high doses of GC and had concurrent
loculated pleural effusions with lung consolidation. Pleu-
ral fluid analyses revealed exudative and neutrophilic in-
flammatory responses without evidence of empyema.
Given their immunosuppression, there was concern for
infection in both cases. Case 1 had just recovered from a
systemic infection with Salmonella, had evidence of in-
fluenza infection in her BAL fluid, had one positive blood
culture for coagulase-negative staphylococci, and did not
respond to antiinfluenza and antistaphylococcal therapies.
Case 2 had a more chronic course of pleurisy but an acute
exacerbation after pulse GC therapy. In addition, case 2
had nodular consolidations on imaging that were of con-
cern for infection and evidence of CMV reactivation in
BAL fluid and plasma. Both cases had evidence for active
SLE with pleurisy, as well as active lupus nephritis with
proteinuria and active urinary sediment. In addition, case
2 had evidence for interstitial pneumonitis with septal
capillary injury and immune deposits that were consistent
with lupus pneumonitis.
DIFFERENTIAL DIAGNOSIS
Infections
Both patients had severe SLE and presented with painful
pleural effusions and lung consolidation while being se-
verely immunosuppressed. The foremost differential diag-
nosis in this clinical context is infection versus active
lupus. Pulmonary infections are common in patients with
SLE and should be a primary consideration in an SLE
patient presenting with respiratory symptoms. Patients
with SLE may be profoundly immunocompromised be-
Gulati et al
cause of immunosuppressive medications and immuno-
dysregulation associated with their underlying disease (1).
Both patients had been receiving prolonged courses of
high-dose GC and also had received other immunosup-
pressive agents such as IV CYC and MMF. They were also
severely lymphopenic (Table 1), likely related to GC and
their underlying disease. Their immunocompromised
states were highlighted by a recent history of salmonellosis
in case 1 and CMV reactivation in case 2. Immunocompro-
mised patients with SLE are at a high risk of pulmonary
infections due to common bacteria, such as Staphylococ-
cus aureus and Streptococcus pneumoniae, but also may
be at risk for opportunistic infections such as Mycobacte-
rium tuberculosis, Nocardia, fungi (including Cryptococ-
cus neoformans and Aspergillus), and P jiroveci (2–7). It is
also important to note that fever may be masked in patients
receiving high doses of GC, and therefore the absence of
fever does not exclude infection.
SLE pleurisy
Pleurisy is the most common pulmonary manifestation of
SLE and occurs in 30 –50% of patients (7). The presenta-
tion varies and may consist of pleuritic chest pain alone
without an effusion. Not infrequently, pleurisy is associ-
ated with pericarditis (pleuropericarditis), which can also
present isolated. SLE pleurisy is thought to be caused by
immune complex deposition in vessels with subsequent
complement activation and direct binding of anti-dsDNA
antibodies to the mesothelium (8 –10). Although rare, ef-
fusions can be unilateral (10,11). Pleural fluid can be lym-
phocytic or neutrophilic and typically has a pH ⬎7.35, as
in both of our cases (12). Complement, ANA, and anti-
dsDNA levels can be measured in pleural fluid and are
helpful in assessing the role of SLE as a cause of pleural
effusion (13,14). Pleural fluid ANA levels are nonspecific,
since they may also be elevated in malignancy, but they
are sensitive. Therefore, the absence of pleural fluid ANA
makes it unlikely that SLE is the cause of a pleural effusion
(15,16). On the other hand, the presence of either anti-
dsDNA antibodies or lupus erythematosus cells (neutro-
phils with ingested nuclear debris appearing as a homog-
enous round inclusion) are diagnostic of SLE, but are not
Clinicopathologic Conference
Table 2. Differential diagnosis of pleuritic chest pain
with or without pleural effusion in patients with SLE*
1. SLE related
Lupus serositis (pleurisy or pericarditis)
Acute lupus pneumonitis
Shrinking lung syndrome
2. Musculoskeletal pain in the rib cage, i.e.,
costochondritis
3. Pulmonary embolism/infarction
4. Infection related
Bacterial pneumonia (empyema or uncomplicated
parapneumonic effusion)
Atypical pneumonia (viral, Mycoplasma pneumoniae,
Legionella species, Chlamydophila pneumoniae)
Pleural tuberculosis
Fungal disease (aspergillosis, histoplasmosis,
cryptococcosis, pneumocystis)
Nocardia/Actinomyces
Subphrenic abscess
5. Drug induced, including drug-induced lupus, i.e.,
due to hydralazine, procainamide, etc.
6. Malignant or paramalignant effusions (non-
Hodgkin’s lymphoma, primary lung cancer, etc.)
7. Selected miscellaneous causes
Uremic pleurisy
Post–cardiac injury syndrome
Ascites (it may represent serositis due to SLE)
Pancreatitis (acute or chronic)
* Effusions without pain may be due to nephrotic syndrome, hy-
poalbuminemia, heart failure, atelectasis, trapped lung (due to pre-
vious severe SLE pleurisy), etc. SLE ⫽ systemic lupus
erythematosus.
sensitive (17,18). In case 2, the pleural fluid was negative
for ANA and lupus erythematosus cells, providing evi-
dence against SLE as the primary etiology of the effusion.
These tests were not performed in case 1. The differential
diagnosis of pleurisy in SLE is shown in Table 2.
Acute lupus pneumonitis (ALP)
Other acute pulmonary manifestations of SLE include ALP
and diffuse alveolar hemorrhage (DAH). ALP is relatively
uncommon, occurring in 1–12% of patients with SLE (19 –
23). The clinical presentation includes cough, pleurisy,
dyspnea, hypoxia, and patchy infiltrates, often with bilat-
eral consolidations that resemble “bronchopneumonia”
(20,21,23). Given the indistinguishable clinical and radio-
graphic presentation from infectious etiologies of pneumo-
nia, establishing the diagnosis requires ruling out infec-
tious processes, often necessitating bronchoscopy. The
histopathology of ALP often shows nonspecific findings,
such as diffuse alveolar damage with hyaline membranes
and interstitial edema (4,19). The presence of vasculitis
and hematoxylin bodies with pleuritis is thought to be
more specific for SLE-induced disease (4,19). DAH is the
most severe acute pulmonary manifestation of SLE. These
patients typically present acutely, as in ALP, and often
present with hemoptysis and a precipitous drop in hemo-
globin. Imaging shows bilateral alveolar infiltrates and
sequential BAL fluid reveals progressively more hemor-
rhagic lavage aliquots. Cytology is notable for hemosider-
in-laden macrophages. Our patients’ presentations and
1009
BAL fluid did not suggest DAH, but they could have been
consistent with ALP. Nevertheless, the largely unilateral
lung involvement and lack of significant hypoxia provided
evidence against ALP.
Chronic interstitial disease
In addition to these acute pulmonary manifestations, SLE
is also associated with chronic interstitial lung disease,
which is seen in 3–13% of patients and typically presents
with dry cough and dyspnea on exertion (7). Radiologic
findings include ground-glass and reticular infiltrates as
well as honeycombing. Associated histologic patterns in-
clude nonspecific interstitial pneumonia, usual interstitial
pneumonia and, less often, lymphocytic interstitial pneu-
monia. In SLE, this entity is associated with anti-Ro anti-
bodies (24 –26). Magro et al have found evidence for mi-
crovascular injury and IgG, IgA, and/or complement
deposition in septal capillaries in patients with chronic
interstitial lung disease in the setting of various collagen
vascular diseases, including anti-Ro–positive SLE (25,26).
The same authors also found reactivity in sera from these
patients against endothelial cells and suggested a possible
pathogenic link between this antibody-mediated (Gell and
Coombs type II immune reaction) microvasculopathy and
pulmonary fibrosis (26). In addition to anti-Ro, other anti-
bodies such as aPL have also been implicated. Similar
microvascular injury and DIF findings were noted on the
TBBX of case 2.
Other potential causes
Another important consideration when dealing with acute
pleurisy in SLE is pulmonary embolism, especially when
patients are positive for aPL or have other risk factors for
thromboembolic disease. Both cases were negative for aPL
and did not have other pulmonary embolism risk factors,
such as intake of oral contraceptives or prolonged immo-
bilization. In addition, pulmonary embolism was excluded
by CT angiography in case 1, and the chronic presentation
of case 2 with marked lung consolidation was not consis-
tent with pulmonary embolism. Another consideration in
the differential diagnosis is malignancy, including bron-
chial carcinoma or lymphoma. However, both of our pa-
tients had disease courses that were marked by acute and
subacute flares of their pleurisy, providing evidence
against this diagnosis and in favor of either active SLE or
infection. The absence of lymphadenopathy on chest CT
scan and a negative history for smoking also provided
evidence against malignancy.
Comparison of cases
In case 1, influenza infection was identified. However,
there was concern for an alternate disease process, partic-
ularly given the dense consolidation and pleural effusion
(both unusual in influenza), the lack of improvement with
oseltamivir, and the broad infectious differential diagno-
sis. The positive blood culture for S warneri was thought to
represent skin contamination because it grew in only one
set of blood cultures and coagulase-negative staphylococci
do not typically cause pneumonia. The 2 most likely eti-
1010
ologies of the presentation of case 1 were thought to be
severe lupus pleurisy with compression atelectasis or
pneumonia due to an unidentified pathogen with associ-
ated parapneumonic effusion/empyema. VATS was there-
fore undertaken to differentiate between these 2 possibil-
ities.
In contrast to case 1, the infiltrates in case 2 appeared to
be true consolidations with distinct nodules. This radio-
graphic appearance, as well as their chronicity and pro-
gression over time, provided evidence for an infection
instead of ALP. The acute clinical deterioration and wors-
ening of the effusion after receiving pulse GC also sup-
ported an infectious etiology. The chronic course of dis-
ease was not typical of bacterial pneumonia, and nodular
infiltrates were more suggestive of fungal, mycobacterial,
and Nocardia infection than PCP or viral processes. The
TBBX in case 2 revealed histologic and DIF features of
chronic interstitial lung disease (26). Her clinical and ra-
diologic presentation, however, was not consistent with
this diagnosis. Therefore, it was unclear if the pathologic
findings represented a concomitant chronic interstitial
lung disease in a preclinical stage or were false-positive in
the setting of inflammation/immune response due to con-
comitant infection.
DISEASE COURSE
Case 1
The patient underwent VATS with decortication and bi-
opsies were taken of the lung and pleura. Grossly, a mod-
erate amount of serous fluid was identified in the pleural
space and a thick pleural rind and pleural adhesions were
also found. The histology of the lung and pleura showed
mild chronic interstitial lung disease and marked reactive
fibrinous pleuritis, respectively (Figure 3). DIF showed IgG
and IgM deposition and complement activation with cap-
illary injury in interalveolar septa. The patient markedly
improved after surgery. She was treated with 1 gm of pulse
IVMP and rituximab (1,000 mg every 2 weeks for 2 doses)
and was discharged on 2,000 mg per day of MMF and 40
Figure 3. Fibrinoid pleuritis with pleural edema and extensive
deposition of fibrin on the pleural surface in case 1.
Gulati et al
Figure 4. Intraoperative granulomas (arrows) noted on the peri-
cardium and diaphragm in case 2.
mg of daily prednisone. Her infiltrate and effusion re-
solved completely within a few months and she was able
to taper her prednisone to 10 mg daily at the last followup,
7 months later.
Case 2
The patient also underwent a VATS with decortication
and biopsies were taken of the lung and pleura. The lung
was strongly adherent to the diaphragm and chest well,
requiring a lengthy blunt dissection. On gross inspection,
the pleural surfaces, pericardium, and diaphragm were
studded with fibrous nodules (Figure 4). Biopsy samples of
both the pleura and lung revealed a neutrophilic, suppu-
rative, organizing granulomatous inflammatory response
with necrotizing abscesses in the setting of a background
of capillary injury and fibrin deposition, as seen previ-
ously on TBBX (Figures 5A and B). Gram stain of the
pleura and pleural fluid revealed branching, beaded gram-
positive rods (Figure 5C), and modified acid-fast Kinyoun
stain revealed partially acid-fast bacilli. Bacterial cultures
subsequently grew Nocardia nova that eventually tested
susceptible to TMP/SMX and carbapenems. At the time of
her second admission to our hospital, it was noted that a
sputum culture that had been sent during her first admis-
sion to our laboratory to detect Legionella had grown
beaded gram-positive rods. Unfortunately, the culture had
been discarded and was not available for further analysis.
After the diagnosis of nocardiosis was made, she was
started on 15 mg/kg of daily TMP/SMX, divided into 3
doses, and 500 mg of IV meropenem every 8 hours. She
continued to receive dual therapy for 6 weeks and then
was transitioned to TMP/SMX oral monotherapy for 1
year. A magnetic resonance image of her brain was normal.
The patient improved rapidly with complete resolution of
infiltrate and effusion within a few months.
DISCUSSION
These cases describe young women with SLE who pre-
sented with pleuritic chest pain, pleural effusion, and
pulmonary infiltrate. This is a relatively common clinical
scenario encountered by physicians who care for patients
Clinicopathologic Conference 1011

Figure 5. A, Areas of neutrophilic and granulomatous inflammation consistent with

an infectious-based etiology in case 2. Adjacent areas of morphologic pattern that
could be interpreted as changes of lupus pneumonitis based on the pattern of pauci-
cellular septal and intraalveolar fibrin deposition are shown. B, Septal and intraal-
veolar fibrin deposition accompanied by red cell extravasation. The process is pauci-
inflammatory. Overall, the pattern of parenchymal injury is characteristic for a Gell
and Coombs type II immune reaction targeting the endothelium. Immunohistochem-
istry showed prominent granular deposition of IgG within the septa of the lungs,
largely localized to the septal capillaries compatible with an anti– endothelial cell
antibody reaction pattern. There was also prominent granular deposition of C5b–9
within the septa. C, Gram-positive branching rods are seen in pleural fluid, consistent
with Nocardia.

with SLE, and our cases offer several instructive points for
their management. Differentiating active lupus from infec-
tion is the main challenge in such cases. This can be very
difficult, since typically many of these patients have active
lupus and at the same time are markedly immunosup-
pressed. A meticulous microbiologic evaluation for infec-
tion, including opportunistic infection, should be per-
formed in all cases. This often requires thoracentesis to
obtain pleural fluid and bronchoscopy to obtain BAL fluid
and TBBX samples. If these tests are negative but there is
still a strong suspicion for infection as in our cases, VATS
may provide a more definitive diagnosis (SLE-associated
fibrinous pleuritis in case 1 and Nocardia infection in case
2).
Adding to the diagnostic challenge, GC, especially at
relatively high doses as in our cases, both alter the presen-
tation of infections and increase the spectra of possible
infectious etiologies. GC impair both innate and acquired
immunity and impair the generation of inflammatory ex-
udates by decreasing the production of various proinflam-
matory mediators (27). Clinically, these effects are mani-
fested by a decreased febrile response and decreased lung
infiltrates and effusions. The fact that the pleural fluid in
case 2 did not have clear features of empyema was possi-
bly related to an antiinflammatory GC effect. Nevertheless,
despite high doses of GC, there was still substantial in-
flammation with development of adhesions and locula-
tions of pleural fluid not only in case 2, but also in case 1,
in which the effusion was not due to infection, but rather
to SLE itself.
The risk of Nocardia infection is significantly increased
in immunocompromised patients, and GC are an indepen-
dent risk factor for nocardiosis (28,29). Lung infections
caused by Nocardia can manifest as single or multiple
lung nodules, reticulonodular infiltrates, lobar consolida-
tions with or without cavitation, and pleural effusions
(30,31). Therefore, nocardiosis should be considered in
immunosuppressed patients with SLE, particularly those
receiving high doses of GC who have unexplained pulmo-
nary infiltrates. The lack of growth of Nocardia on BAL
fluid and TBBX cultures in case 2 demonstrates the fastid-
ious nature of Nocardia and the difficulty in cultivating
these organisms by conventional cultures. These proper-
ties explain why the time from onset of symptoms until
diagnosis of pulmonary nocardiosis is typically more than
1 month (32). In case 2, the initiation of prophylactic
TMP/SMX 2 days prior to the bronchoscopy may also have
decreased the culture yield. If infection with Nocardia is
suspected, clinicians should ask the microbiology labora-
tory to perform a modified acid-fast stain on respiratory
specimens that uses a weaker acid as a decolorizer rather
than a full acid-fast stain. This modification to the conven-
tional acid-fast stain allows the moderately acid-fast No-
cardia to retain the initial stain and to be visualized (33).
Although routine aerobic culture media can support No-
cardia, clinicians can also ask for selective media, such as
1012
buffered charcoal yeast extract that is used to isolate Le-
gionella. These media are beneficial to support Nocardia
because they decrease the overgrowth of other organisms
in specimens obtained from nonsterile sites (33). In case 2,
a sputum specimen obtained before initiation of TMP/
SMX prophylaxis during her initial hospitalization in our
institution that was sent for Legionella culture grew gram-
positive rods, which was the first clue that suggested no-
cardiosis. This case also highlights that Nocardia are not a
component of the normal respiratory flora and should be
considered a pathogen when grown from any respiratory
specimen (33). Finally, if Nocardia are suspected, the mi-
crobiology laboratory should be instructed to hold respi-
ratory specimens for an extended period of time. Respira-
tory cultures are often discarded at 48 –72 hours, and
Nocardia often require a longer incubation period to grow
(33).
Although there are no randomized trials to determine
the optimal treatment of nocardiosis, sulfonamides, such
as TMP/SMX, are considered the standard of therapy.
However, most authorities recommend initial combination
therapy, particularly given recent reports of emerging re-
sistance to TMP/SMX (34,35). Although clinical improve-
ment is typically noted within 2 weeks of initiating ther-
apy, prolonged antibiotic courses of up to 12 months are
recommended because of high rates of relapse. Nocardia
often invade blood vessels and have a propensity to cause
brain infections. In fact, the central nervous system (CNS)
is the most common extrapulmonary location for nocardi-
osis (28). Therefore, any symptoms of CNS disease warrant
brain imaging to exclude brain abscess, and many author-
ities recommend brain imaging in all immunocompro-
mised hosts with Nocardia (34). Fortunately, case 2 did
not have CNS lesions on imaging. Case 2 had a dramatic
response to antibiotics and is expected to complete a full
year of therapy with TMP/SMX.
Mild pleurisy due to active SLE is treated first with
nonsteroidal antiinflammatory drugs (NSAIDs) (7). How-
ever, if the presentation is severe (as in our cases), or if the
patient does not respond to NSAIDs in a few days, mod-
erate to high doses of GC may be used (7). The most severe
cases may also be treated with IV pulse GC. In rare cases
where GC cannot be tapered because of severe (such as in
our case 1) or recurrent inflammation, other immunosup-
pressive agents, such as azathioprine and MMF, may be
needed. Tetracycline or talc pleurodesis have been used
for recurrent large effusions (7). Of note, uncontrolled
pleural inflammation may lead to fibrothorax and trapped
lung (7,36). Our case 1 responded dramatically to decorti-
cation, supporting its therapeutic role in severe forms of
this disease.
The discrepant diagnoses from these 2 similar case pre-
sentations provide evidence for early consideration of
VATS to distinguish between infection and SLE-associ-
ated pleurisy. Despite extensive evaluations with imaging,
bronchoscopy, and pathology (using 2 different sampling
techniques in case 2, specifically, percutaneous CT-guided
needle biopsy and TBBX), the correct diagnoses were not
identified and therefore, appropriate care was delayed. Not
only does VATS offer diagnostic value, it may have a
therapeutic benefit (7,36). Case 1 improved rapidly after
Gulati et al
VATS, before one would expect a benefit from rituximab
or an increased dose of MMF. In case 2, the diagnosis was
not made until VATS was performed. These cases high-
light the important role of VATS in patients with SLE and
pulmonary pathology of unclear etiology despite less in-
vasive diagnostic procedures.
FINAL DIAGNOSIS
Case 1
Marked reactive fibrinous pleuritis due to active SLE with
compression atelectasis of the adjacent lung. Mild chronic
interstitial lung disease due to SLE.
Case 2
Pneumonia and empyema due to Nocardia nova infection.
Possible interstitial lung disease due to SLE.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors ap-
proved the final version to be published. Dr. Kirou had full access
to all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Study conception and design. Gulati, Magro, Kirou.
Acquisition of data. Gulati, Satlin, Magro, Kirou.
Analysis and interpretation of data. Gulati, Magro, Kirou.
REFERENCES
1. Zandman-Goddard G, Shoenfeld Y. Infections and SLE. Au-
toimmunity 2005;38:473– 85.
2. Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, Martinez-Ber-
riotxoa A, Egurbide MV, Aguirre C. Predictors of major infec-
tions in systemic lupus erythematosus. Arthritis Res Ther
2009;11:R109.
3. Chen HS, Tsai WP, Leu HS, Ho HH, Liou LB. Invasive fungal
infection in systemic lupus erythematosus: an analysis of 15
cases and a literature review. Rheumatology (Oxford) 2007;
46:539 – 44.
4. Quadrelli SA, Alvarez C, Arce SC, Paz L, Sarano J, Sobrino
EM, et al. Pulmonary involvement of systemic lupus
erythematosus: analysis of 90 necropsies. Lupus 2009;18:
1053– 60.
5. Jick SS, Lieberman ES, Rahman MU, Choi HK. Glucocorticoid
use, other associated factors, and the risk of tuberculosis.
Arthritis Rheum 2006;55:19 –26.
6. Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive
fungal infections. Lancet 2003;362:1828 –38.
7. Kamen DL, Strange C. Pulmonary manifestations of systemic
lupus erythematosus. Clin Chest Med 2010;31:479 – 88.
8. Balbir-Gurman A, Yigla M, Nahir AM, Braun-Moscovici Y.
Rheumatoid pleural effusion. Semin Arthritis Rheum 2006;
35:368 –78.
9. Guo H, Leung JC, Chan LY, Chan TM, Lai KN. The pathoge-
netic role of immunoglobulin G from patients with systemic
lupus erythematosus in the development of lupus pleuritis.
Rheumatology (Oxford) 2004;43:286 –93.
10. Man BL, Mok CC. Serositis related to systemic lupus
erythematosus: prevalence and outcome. Lupus 2005;14:
822– 6.
11. Swigris JJ, Fischer A, Gillis J, Meehan RT, Brown KK. Pulmo-
nary and thrombotic manifestations of systemic lupus ery-
thematosus. Chest 2008;133:271– 80.
12. Segal AM, Calabrese LH, Ahmad M, Tubbs RR, White CS. The
pulmonary manifestations of systemic lupus erythematosus.
Semin Arthritis Rheum 1985;14:202–24.
Clinicopathologic Conference
13. Toworakul C, Kasitanon N, Sukitawut W, Wichinun R, Lou-
threnoo W. Usefulness of pleural effusion antinuclear anti-
bodies in the diagnosis of lupus pleuritis. Lupus 2011;20:
1042– 6.
14. Good JT Jr, King TE, Antony VB, Sahn SA. Lupus pleuritis:
clinical features and pleural fluid characteristics with special
reference to pleural fluid antinuclear antibodies. Chest 1983;
84:714 – 8.
15. Wang DY, Yang PC, Yu WL, Kuo SH, Hsu NY. Serial antinu-
clear antibodies titre in pleural and pericardial fluid. Eur
Respir J 2000;15:1106 –10.
16. Swissa M, Amital-Teplizki H, Haim N, Cohen Y, Shoenfeld Y.
Autoantibodies in neoplasia: an unresolved enigma. Cancer
1990;65:2554 – 8.
17. Halla JT, Schrohenloher RE, Volanakis JE. Immune complexes
and other laboratory features of pleural effusions: a compar-
ison of rheumatoid arthritis, systemic lupus erythematosus,
and other diseases. Ann Intern Med 1980;92:748 –52.
18. Riska H, Fyhrquist F, Selander RK, Hellstrom PE. Systemic
lupus erythematosus and DNA antibodies in pleural effu-
sions. Scand J Rheumatol 1978;7:159 – 60.
19. Haupt HM, Moore GW, Hutchins GM. The lung in systemic
lupus erythematosus: analysis of the pathologic changes in
120 patients. Am J Med 1981;71:791– 8.
20. Mayberry JP, Primack SL, Muller NL. Thoracic manifestations
of systemic autoimmune diseases: radiographic and high-res-
olution CT findings. Radiographics 2000;20:1623–35.
21. Matthay RA, Schwarz MI, Petty TL, Stanford RE, Gupta RC,
Sahn SA, et al. Pulmonary manifestations of systemic lupus
erythematosus: review of twelve cases of acute lupus pneu-
monitis. Medicine (Baltimore) 1975;54:397– 409.
22. Levin DC. Proper interpretation of pulmonary roentgen
changes in systemic lupus erythematosus. Am J Roentgenol
Radium Ther Nucl Med 1971;111:510 –7.
23. Murin S, Wiedemann HP, Matthay RA. Pulmonary manifes-
tations of systemic lupus erythematosus. Clin Chest Med
1998;19:641– 65.
24. Hedgpeth MT, Boulware DW. Interstitial pneumonitis in an-
tinuclear antibody–negative systemic lupus erythematosus: a
1013
new clinical manifestation and possible association with
anti–Ro (SS-A) antibodies. Arthritis Rheum 1988;31:545– 8.
25. Magro CM, Crowson AN. The cutaneous pathology associated
with seropositivity for antibodies to SSA (Ro): a clinicopath-
ologic study of 23 adult patients without subacute cutaneous
lupus erythematosus. Am J Dermatopathol 1999;21:129 –37.
26. Magro CM, Ross P, Marsh CB, Allen JN, Liff D, Knight DA, et
al. The role of anti-endothelial cell antibody-mediated micro-
vascular injury in the evolution of pulmonary fibrosis in the
setting of collagen vascular disease. Am J Clin Pathol 2007;
127:237– 47.
27. Chatham WW, Kimberly RP. Treatment of lupus with corti-
costeroids. Lupus 2001;10:140 –7.
28. Beaman BL, Beaman L. Nocardia species: host-parasite rela-
tionships. Clin Microbiol Rev 1994;7:213– 64.
29. Peleg AY, Husain S, Qureshi ZA, Silveira FP, Sarumi M, Shutt
KA, et al. Risk factors, clinical characteristics, and outcome of
Nocardia infection in organ transplant recipients: a matched
case-control study. Clin Infect Dis 2007;44:1307–14.
30. Mok CC, Yuen KY, Lau CS. Nocardiosis in systemic lupus
erythematosus. Semin Arthritis Rheum 1997;26:675– 83.
31. Palmer DL, Harvey RL, Wheeler JK. Diagnostic and therapeu-
tic considerations in Nocardia asteroides infection. Medicine
(Baltimore) 1974;53:391– 401.
32. Martinez Tomas R, Menendez Villanueva R, Reyes Calzada S,
Santos Durantez M, Valles Tarazona JM, Modesto Alapont M,
et al. Pulmonary nocardiosis: risk factors and outcomes. Re-
spirology 2007;12:394 – 400.
33. McNeil MM, Brown JM. The medically important aerobic
actinomycetes: epidemiology and microbiology. Clin Micro-
biol Rev 1994;7:357– 417.
34. Wilson JW. Nocardiosis: updates and clinical overview. Mayo
Clin Proc 2012;87:403–7.
35. Uhde KB, Pathak S, McCullum I Jr, Jannat-Khah DP, Shadomy
SV, Dykewicz CA, et al. Antimicrobial-resistant nocardia iso-
lates, United States, 1995-2004. Clin Infect Dis 2010;51:
1445– 8.
36. Sharma S, Smith R, Al-Hameed F. Fibrothorax and severe
lung restriction secondary to lupus pleuritis and its success-
ful treatment by pleurectomy. Can Respir J 2002;9:335–7.